The Experts below are selected from a list of 102 Experts worldwide ranked by ideXlab platform
Bert W Omalley - One of the best experts on this subject based on the ideXlab platform.
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Nuclear Receptor Coregulators in cancer biology
Cancer Research, 2009Co-Authors: Bert W Omalley, Rakesh KumarAbstract:Coregulators (coactivators and corepressors) occupy the driving seat for actions of all Nuclear Receptors, and consequently, selective Receptor modulator drugs. The potency and selectivity for subreactions of transcription reside in the coactivators, and thus, they are critically important for tissue-selective gene function. Each tissue has a "quantitative finger print" of coactivators based on its relative inherited concentrations of these molecules. When the cellular concentration of a coactivator is altered, genetic dysfunction usually leads to a pathologic outcome. For example, many cancers overexpress "growth coactivators." In this way, the cancer cell can hijack these coactivator molecules to drive proliferation and metastasis. The present review contains summaries of selective coactivators and corepressors that have been demonstrated to play important roles in the malignant process and emphasizes their importance for future therapeutic interventions.
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Nuclear Receptor Coregulators and human disease
Endocrine Reviews, 2008Co-Authors: David M. Lonard, Rainer B Lanz, Bert W OmalleyAbstract:Nuclear Receptor (NR) Coregulators (coactivators and corepressors) are essential elements in regulating Nuclear Receptor-mediated transcription. In a little more than a decade since their discovery, these proteins have been studied mechanistically and reveal that the regulation of transcription is a highly controlled and complex process. Because of their central role in regulating NR-mediated transcription and in coordinating intercompartmental metabolic processes, disruptions in coregulator biology can lead to pathological states. To date, the extent to which they are involved in human disease has not been widely appreciated. In a complete literature survey, we have identified nearly 300 distinct Coregulators, revealing that a great variety of enzymatic and regulatory capabilities exist for NRs to regulate transcription and other cellular events. Here, we substantiate that Coregulators are broadly implicated in human pathological states and will be of growing future interest in clinical medicine.
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a subset of Nuclear Receptor Coregulators act as coupling proteins during synthesis and maturation of rna transcripts
Molecular and Cellular Biology, 2005Co-Authors: Didier Auboeuf, Dennis H Dowhan, Martin Dutertre, Natalia Martin, Susan M Berget, Bert W OmalleyAbstract:Gene expression is a multistep process starting in the cell nucleus with the synthesis of the primary transcripts that undergo several modifications (including capping, splicing, and polyadenylation) leading to the export of the mature mRNAs into the cytoplasm for translation into proteins. Although an emerging view is that all the steps from transcription to translation are mechanically and functionally coupled, the proteins that are involved in this coupled process are still poorly characterized. In recent years, a growing list of proteins known to control gene expression at the transcriptional level, named transcriptional Coregulators, have been independently shown to play additional roles in other steps of gene expression. In this review we compile these emerging data suggesting that a subset of transcriptional Coregulators play a major role in the coordination of the individual steps of the gene expression process.
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Nuclear Receptor Coregulators
Pure and Applied Chemistry, 2003Co-Authors: Neil J Mckenna, Bert W OmalleyAbstract:It has been postulated that Nuclear Receptors (NRs) regulate transcription via inter- actions with chromatin and the basal transcription machinery at the promoters of genes. Coregulators (coactivators or corepressors) are important in mediating these interactions and thereby modulating positive or negative Receptor activity. A large number of putative coacti- vators have been isolated, several of which will be reviewed with respect to certain "criteria" initially proposed for coactivators. We will discuss, with reference to in vitro and in vivo ex- periments, the main steps in initiation that are influenced by coactivators: (1) initiation (e.g., SRC-1 family, CBP); (2) repetitive transcription (e.g., TRAPs/DRIPs); (3) RNA processing (PGC-1, etc); and (4) termination/turnover (E6-AP, etc). A variety of enzyme functions have been implicated in the coactivator complex including acetylase, methylase, ubiquitin ligase, kinase, and phosphatase activities. Moreover, coactivators and corepressors appear to exist in the steady-state cell as a series of multiprotein complexes referred to collectively as the "Coregulatorsome". Different subcomplexes within the Coregulatorsome may have different levels of preference for individual Receptors or promoters, likely contributing to context-spe- cific functions of NRs in target tissues.
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sequentiality and processivity of Nuclear Receptor Coregulators in regulation of target gene expression
Nuclear Receptor Signaling, 2003Co-Authors: Bert W OmalleyAbstract:A series of data has accumulated over the past five years that raises questions about our current understanding of the transcriptional process and its regulation. Following the discovery of coactivators for Nuclear Receptors (NRs), a large number of these molecules have been reported in the literature. This perspective will summarize some opinions on the significance of this large number of factors.
Bert W. O'malley - One of the best experts on this subject based on the ideXlab platform.
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The dynamics of Nuclear Receptors and Nuclear Receptor Coregulators in the pathogenesis of endometriosis
Human reproduction update, 2014Co-Authors: Sang Jun Han, Bert W. O'malleyAbstract:background: Endometriosis is defined as the colonization and growth of endometrial tissue at anatomic sites outside the uterine cavity. Up to 15% of reproductive-aged women in the USA suffer from painful symptoms of endometriosis, such as infertility, pelvic pain, menstrual cycle abnormalities and increased risk of certain cancers. However, many of the current clinical treatments for endometriosis are not sufficiently effect- ive and yield unacceptable side effects. There is clearly an urgent need to identify new molecular mechanisms that critically underpin the initiation and progression of endometriosis in order to develop more specific and effective therapeutics which lack the side effects of current therapies. The aim of this review is to discuss how Nuclear Receptors (NRs) and their Coregulators promote the progression of endometriosis. Understanding the pathogenic molecular mechanisms for the genesis and maintenance of endometriosis as modulated by NRs and Coregulators can reveal new thera- peutic targets for alternative endometriosis treatments. methods: This review was prepared using published gene expression microarray data sets obtained from patients with endometriosis and published literature on NRs and their Coregulators that deal with endometriosis progression. Using the above observations, our current under- standing of how NRs and NR Coregulators are involved in the progression of endometriosis is summarized. results: Aberrant levels of NRs and NR Coregulators in ectopic endometriosis lesions are associated with the progression of endometriosis. As an example, endometriotic cell-specific alterations in gene expression are correlated with a differential methylation status of the genome com- pared with the normal endometrium. These differential epigenetic regulations can generate favorable cell-specific NR and coregulator milieus for endometriosis progression. Genetic alterations, such as single nucleotide polymorphisms and insertion/deletion polymorphisms of NR and cor- egulator genes, are frequently detected in ectopic lesions compared with the normal endometrium. These genetic variations impart new molecu- lar properties to NRs and Coregulators to increase their capacity to stimulate progression of endometriosis. Finally, post-translational modifications of NR Coregulators, such as proteolytic processing, generate endometriosis-specific isoforms. Compared with the unmodified Coregulators, these coregulator isoforms have unique functions that enhance the pathogenesis of endometriosis.
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Nuclear Receptor Coregulators: modulators of pathology and therapeutic targets
Nature reviews. Endocrinology, 2012Co-Authors: David M. Lonard, Bert W. O'malleyAbstract:The Nuclear Receptor superfamily includes transcription factors that transduce steroid, thyroid and retinoid hormones and other ligands in conjunction with Coregulators. To date, over 350 Coregulators have been reported in the literature, and advances in proteomic analyses of coregulator protein complexes have revealed that a far greater number of coregulator-interacting proteins also exist. Coregulator dysfunction has been implicated in diverse pathological states, genetic syndromes and cancer. A hallmark of disease related to the disruption of normal coregulator function is the pleiotropic effect on animal physiology, which is frequently manifested as the dysregulation of metabolic and neurological systems. Coregulators have broad physiological and pathological functions that make them promising new drug targets for diseases such as hormone-dependent cancers. Advances in proteomics, genomics and transcriptomics have provided novel insights into the biology of Coregulators at a system-wide level and will lead the way to a new understanding of how Coregulators can be evaluated in the context of complex and multifaceted genetic factors, hormones, diet, the environment and stress. Ultimately, better knowledge of the associations that exist between coregulator function and human diseases is expected to expand the indications for the use of future coregulator-targeted drugs.
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Nuclear Receptor Coregulators: Judges, Juries, and Executioners of Cellular Regulation
Molecular cell, 2007Co-Authors: David M. Lonard, Bert W. O'malleyAbstract:In a little more than 10 years, Nuclear Receptor (NR) Coregulators (coactivators and corepressors) have contributed to our present realization that a great level of sophistication exists in transcriptional regulation. Here, we discuss the implications of Coregulators as versatile regulatory agents, influencing not only transcriptional initiation but also elongation, splicing, and translation. In addition to this, there is an increasing recognition that they also regulate a variety of biological processes outside of the nucleus. An important concept that we wish to emphasize is that Coregulators are both targets and propagators of posttranslational modification (PTM) codes. This underlies a sophisticated epigenetic regulatory scheme from which a complex and dynamic mammalian phenotype emanates.
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Nuclear Receptor Coregulators are new players in nervous system development and function.
Molecular neurobiology, 2004Co-Authors: Eijun Nishihara, Bert W. O'malleyAbstract:Steroid/thyroid hormones and their cognate Nuclear Receptors (NRs) play important roles in nervous system development and function. The spatial and temporal gene expression that is regulated by NRs in the nervous system requires transcriptional intermediary coregualtors, designated as coactivators and corepressors. These Coregulators enhance or repress transcriptional activity of NRs and modulate their target gene transcription. Recent progress has largely advanced our understanding of the molecular mechanisms by which NR Coregulators function in the nervous system. This article summarizes our current knowledge about the molecular mechanisms, expression patterns, and biological functions of NR coactivators, such as the p160 steroid Receptor coactivator family, CBP, p300, BRG1, TRAP220, PGC-1α, ERAP140, NIX1, and E6-AP, as well as corepressors such as NCoR and SMRT. Accumulated findings suggest that the functional spectrum of NR Coregulators is much broader than was initially speculated, and these Coregulators likely contribute to many physiological aspects of nervous system development and function.
Rainer B Lanz - One of the best experts on this subject based on the ideXlab platform.
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Nuclear Receptor Coregulators and human disease
Endocrine Reviews, 2008Co-Authors: David M. Lonard, Rainer B Lanz, Bert W OmalleyAbstract:Nuclear Receptor (NR) Coregulators (coactivators and corepressors) are essential elements in regulating Nuclear Receptor-mediated transcription. In a little more than a decade since their discovery, these proteins have been studied mechanistically and reveal that the regulation of transcription is a highly controlled and complex process. Because of their central role in regulating NR-mediated transcription and in coordinating intercompartmental metabolic processes, disruptions in coregulator biology can lead to pathological states. To date, the extent to which they are involved in human disease has not been widely appreciated. In a complete literature survey, we have identified nearly 300 distinct Coregulators, revealing that a great variety of enzymatic and regulatory capabilities exist for NRs to regulate transcription and other cellular events. Here, we substantiate that Coregulators are broadly implicated in human pathological states and will be of growing future interest in clinical medicine.
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Nuclear Receptor Coregulators cellular and molecular biology
Endocrine Reviews, 1999Co-Authors: Neil J Mckenna, Rainer B Lanz, Bert W OmalleyAbstract:I. Introduction A. The Nuclear Receptor superfamily B. General transcription factors (GTFs) II. Nuclear Receptor Coactivators A. Background B. Receptor-associated proteins and coactivators III. Nuclear Receptor Corepressors A. Background B. Corepressors IV. Nuclear Receptors and Chromatin A. Background B. The MMTV and TRβA promoters C. Coactivators and acetylation D. Chromatin-remodeling proteins E. Corepressors and deacetylation V. Concluding Remarks
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Nuclear Receptor Coregulators: Cellular and molecular biology
Endocrine Reviews, 1999Co-Authors: N. J. Mckenna, Rainer B Lanz, B W O'malleyAbstract:Nuclear Receptor Coregulators are coactivators or corepressors that are required by Nuclear Receptors for efficient transcripitonal regulation. In this context, we define coactivators, broadly, as molecules that interact with Nuclear Receptors and enhance their transactivation. Analogously, we refer to Nuclear Receptor corepressors as factors that interact with Nuclear Receptors and lower the transcription rate at their target genes. Most Coregulators are, by definition, rate limiting for Nuclear Receptor activation and repression, but do not significantly alter basal transcription. Recent data have indicated multiple modes of action of Coregulators, including direct interactions with basal transcription factors and covalent modification of histones and other proteins. Reflecting this functional diversity, many Coregulators exist in distinct steady state precomplexes, which are thought to associate in promoter-specific configurations. In addition, these factors may function as molecular gates to enable integration of diverse signal transduction pathways at Nuclear Receptor-regulated promoters. This review will summarize selected aspects of our current knowledge of the cellular and molecular biology of Nuclear Receptor Coregulators.
Chinyo Lin - One of the best experts on this subject based on the ideXlab platform.
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differential recruitment of Nuclear Receptor Coregulators in ligand dependent transcriptional repression by estrogen Receptor α
Oncogene, 2011Co-Authors: K W Merrell, J D Crofts, R L Smith, J H Sin, K E Kmetzsch, A Merrell, R O Miguel, N R Candelaria, Chinyo LinAbstract:Estrogen Receptors (ERs) are normally expressed in breast tissues and mediate hormonal functions during development and in female reproductive physiology. In the majority of breast cancers, ERs are involved in regulating tumor cell proliferation and serve as prognostic markers and therapeutic targets in the management of hormone-dependent tumors. At the molecular level, ERs function as ligand-dependent transcription factors and activate target-gene expression following hormone stimulation. Recent transcriptomic and whole-genome-binding studies suggest, however, that ligand-activated ERs can also repress the expression of a significant subset of target genes. To characterize the molecular mechanisms of transcriptional repression by ERs, we examined recruitment of Nuclear Receptor Coregulators, histone modifications and RNA polymerase II docking at ER-binding sites and cis-regulatory regions adjacent to repressed target genes. Moreover, we utilized gene expression data from patient samples to determine potential roles of repressed target genes in breast cancer biology. Results from these studies indicate that Nuclear Receptor corepressor recruitment is a key feature of ligand-dependent transcriptional repression by Ers, and some repressed target genes are associated with disease progression and response to endocrine therapy. These findings provide preliminary insights into a novel aspect of the molecular mechanisms of ER functions and their potential roles in hormonal carcinogenesis and breast cancer biology.
B W O'malley - One of the best experts on this subject based on the ideXlab platform.
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Nuclear Receptor Coregulators: Cellular and molecular biology
Endocrine Reviews, 1999Co-Authors: N. J. Mckenna, Rainer B Lanz, B W O'malleyAbstract:Nuclear Receptor Coregulators are coactivators or corepressors that are required by Nuclear Receptors for efficient transcripitonal regulation. In this context, we define coactivators, broadly, as molecules that interact with Nuclear Receptors and enhance their transactivation. Analogously, we refer to Nuclear Receptor corepressors as factors that interact with Nuclear Receptors and lower the transcription rate at their target genes. Most Coregulators are, by definition, rate limiting for Nuclear Receptor activation and repression, but do not significantly alter basal transcription. Recent data have indicated multiple modes of action of Coregulators, including direct interactions with basal transcription factors and covalent modification of histones and other proteins. Reflecting this functional diversity, many Coregulators exist in distinct steady state precomplexes, which are thought to associate in promoter-specific configurations. In addition, these factors may function as molecular gates to enable integration of diverse signal transduction pathways at Nuclear Receptor-regulated promoters. This review will summarize selected aspects of our current knowledge of the cellular and molecular biology of Nuclear Receptor Coregulators.
